title: Insulinoma-released exosomes activate autoreactive marginal zone-like B cells that expand endogenously in prediabetic NOD mice.
abstract: Exosomes (EXOs) are nano-sized secreted microvesicles that can function as potent endogenous carriers of adjuvant and antigens. To examine a possible role in autoimmunity for EXOs, we studied EXO-induced immune responses in nonobese diabetic (NOD) mice, an autoimmune-prone strain with tissue-specific targeting at insulin-secreting beta cells. EXOs released by insulinoma cells can activate various antigen-presenting cells to secrete several proinflammatory cytokines and chemokines. A subset of B cells responded to EXO stimulation in culture by proliferation, and expressed surface markers representing marginal zone B cells, which was independent of T helper cells. Importantly, splenic B cells from prediabetic NOD mice, but not diabetic-resistant mice, exhibited increased reactivity to EXOs, which was correlated with a high level of serum EXOs. We found that MyD88-mediated innate TLR signals were essential for the B-cell response; transgenic B cells expressing surface immunoglobulin specific for insulin reacted to EXO stimulation, and addition of a calcineurin inhibitor FK506 abrogated the EXO-induced B-cell response, suggesting that both innate and antigen-specific signals may be involved. Thus, EXOs may contribute to the development of autoimmunity and type 1 diabetes in NOD mice, partially via activating autoreactive marginal zone-like B cells.
authors.affiliation: Division of Immune Regulation, Torrey Pines Institute for Molecular Studies, San Diego, CA, USA.
authors.forename: Roman
authors.initials: R
authors.lastname: Bashratyan
authors.forename: Huiming
authors.initials: H
authors.lastname: Sheng
authors.forename: Danielle
authors.initials: D
authors.lastname: Regn
authors.forename: M Jubayer
authors.initials: MJ
authors.lastname: Rahman
authors.forename: Yang D
authors.initials: YD
authors.lastname: Dai
mesh_terms: D000818:Animals; D001324:Autoantigens / Q000276:immunology; D001402:B-Lymphocytes / Q000276:immunology*; D049109:Cell Proliferation / Q000187:drug effects; D002478:Cells, Cultured; D016207:Cytokines / Q000378:metabolism; D003921:Diabetes Mellitus, Experimental / Q000276:immunology*; D004198:Disease Susceptibility; D055354:Exosomes / Q000276:immunology* / Q000378:metabolism; D007136:Immunoglobulins / Q000235:genetics / Q000378:metabolism; D018836:Inflammation Mediators / Q000378:metabolism; D007328:Insulin / Q000276:immunology; D008213:Lymphocyte Activation / Q000187:drug effects / Q000235:genetics; D051379:Mice; D016688:Mice, Inbred NOD; D053594:Myeloid Differentiation Factor 88 / Q000378:metabolism; D054448:Precursor Cells, B-Lymphoid / Q000276:immunology*; D015398:Signal Transduction / Q000187:drug effects / Q000235:genetics; D016559:Tacrolimus / Q000494:pharmacology; D051193:Toll-Like Receptors / Q000378:metabolism
chemical_list: D001324:Autoantigens; D016207:Cytokines; D007136:Immunoglobulins; D018836:Inflammation Mediators; D007328:Insulin; D053594:Myeloid Differentiation Factor 88; D051193:Toll-Like Receptors; D016559:Tacrolimus
keywords: Autoimmunity; Autoreactive B cells; Exosomes; NOD; type 1 diabetes (T1D)